SUMMARY SIRT6 is a longevity gene. SIRT6 KO mice exhibit premature aging and genomic instability, while SIRT6 overexpressing mice show lifespan extension. SIRT6 regulates glucose homeostasis, controls inflammation, and promotes DNA repair. Several lines of evidence support the role of SIRT6 in preventing Alzheimer?s disease (AD): (1) brain-specific SIRT6 KO mice develop neurodegeneration; (2) SIRT6 levels are lower in AD patients; (3) SIRT6 is a central regulator of DNA repair and links between compromised DNA repair and AD have been proposed; (4) AD is associated with neuroinflammation, while our recent data shows that SIRT6 suppresses inflammation; (5) Furthermore, we recently demonstrated that SIRT6 allele found in human centenarians has enhanced enzymatic activity and that SIRT6 activity positively correlates with species? lifespan. Based on these finding, we hypothesize that activating SIRT6 confers protection from AD by improving DNA repair and suppressing inflammation. The goal of the parent R01 grant is to examine the role of SIRT6 in longevity. Here we propose to expand our work into AD field by testing whether SIRT6 activators confer protection from AD using mouse models. SIRT6 has two enzymatic activities, deacetylation and mono-ADP-ribosylation. Several chemical activators of SIRT6 deacetylation activity have been reported. We have tested the effect of these activators on SIRT6 mono-ADP-ribosylation activity and identified fucoidan as the most potent activator of SIRT6 mono-ADP ribosylation activity, which is required for SIRT6 function in reducing inflammation and stimulating DNA repair. Our preliminary experiments suggest that fucoidan enhances DNA repair in cultured cells. Fucoidan is a short polysaccharide found in brown seaweed. Intriguingly, seaweed is widely consumed in Japan, a country with the highest life expectancy. Here we propose to test whether fucoidan and other activators of SIRT6 mono-ADP-ribosylation activity: (1) Protect neuronal and microglial cells from DNA damage and reduce inflammation; (2) Alleviate pathology in AD mouse models. We will treat MAPT and 5xFAD AD mouse models with SIRT6 activators. We selected the two AD strains to evaluate the effect of SIRT6 activators on intracellular pathology, the neurofibrillary tangles, seen in MAPT model as well as the extracellular pathology, the amyloid plaques, seen in 5xFAD model. These experiments will serve as a proof of principle that activating SIRT6 may be used as therapeutic strategy against AD. Furthermore, these studies may directly lead to novel AD therapies using SIRT6 chemical activators.